My career goal is to develop the experience, skills, and infrastructure to become an independent investigator in smoking cessation research with a focus on molecular genetics. This K08 Mentored Clinical Scientist Award proposal outlines a comprehensive, five-year program of supervised research in pharmacogenetic smoking cessation clinical trials with Sponsors Raymond Niaura, Ph.D. at Brown University, and Co-Sponsor Peter Shields, M.D. at Georgetown University, a structured didactic seminar series integrated with the Transdisciplinary Tobacco Use Research Center at Brown University combined with laboratory training in genotyping techniques at Georgetown University and establishment of an independent laboratory at Brown University. This work will be informed by an outstanding network of transdisciplinary mentors and collaborative research with Co-Sponsors at the University of Oxford. The focus of the proposed research is an evaluation of the role of the dopamine transporter SLC6A3 polymorphism, and other dopaminergic candidate gene polymorphisms, in treatment response of smokers to bupropion hydrochloride for smoking cessation. The proposed research would be the first study to explore how genotype and treatment interact through multiple cognitive, behavioral, affective, and physiological endophenotypes to reduce the reinforcing properties of smoking and impact smoking outcomes. The specific aims are: (1) To evaluate the role of the dopamine transporter SLC6A3 polymorphism in treatment response to bupropion for smoking cessation, (2) To test the hypotheses that bupropion diminishes the reinforcing properties of smoking and that the effect of bupropion on reduction of the reinforcing properties of smoking will be significantly greater among smokers who carry DRD2-Taq1 A2/A2 genotypes than it is among smokers with DRD2-Taq1 A1/A1 or A1/A2 genotypes, (3) To investigate the interaction between genotype and cue reactivity among smokers with DRD2-Taq1 A2/A2 and DRD2-Taq1 A1/A1 or A1/A2 genotypes, and (4) To evaluate the impact of additional dopaminergic candidate gene polymorphisms on treatment response to bupropion for smoking cessation and multiple endophenotypes.